PRINCIPAL DISPLAY PANEL

Rydapt®

NDC 0078-0698-99

(midostaurin)
Capsules

25 mg

Rx only

56 soft capsules

Contents: 2 packs containing 28 capsules each

NOVARTIS

14 CLINICAL STUDIES

14.1 Acute Myeloid Leukemia

Study 1

RYDAPT in combination with chemotherapy was investigated in a randomized, double-blind placebo-controlled trial of 717 patients with newly-diagnosed FLT3-mutated AML. In this study, FLT3 mutation status was determined prospectively with a clinical trial assay and verified retrospectively using the companion diagnostic LeukoStrat® CDx FLT3 Mutation Assay, which is an FDA- approved test for selection of patients with AML for RYDAPT treatment. Patients were stratified by FLT3 mutation status: TKD, ITD with allelic ratio less than 0.7, and ITD with allelic ratio greater than or equal to 0.7. Patients with acute promyelocytic leukemia or therapy-related AML were not eligible. Patients were randomized (1:1) to receive RYDAPT 50 mg twice daily (n = 360) or placebo (n = 357) with food on Days 8 to 21 in combination with daunorubicin (60 mg/m2 daily on Days 1 to 3) /cytarabine (200 mg/m2 daily on Days 1 to 7) for up to two cycles of induction and high dose cytarabine (3 g/m2 every 12 hours on Days 1, 3, and 5) for up to four cycles of consolidation, followed by continuous RYDAPT or placebo treatment according to initial assignment for up to 12 additional 28-day cycles. There was no re- randomization at the start of post consolidation therapy. Patients who proceeded to hematopoietic stem cell transplantation (SCT) stopped receiving study treatment.

The randomized patients had a median age of 47 years (range, 18 to 60 years), 44% were male, and 88% had a performance status of 0-1. AML was de novo onset in 95%. The percentage of patients with FLT3-ITD allelic ratio < 0.7, FLT3-ITD allelic ratio ≥ 0.7, and FLT3-TKD mutations were identical (per randomized FLT3 stratum) on both arms (48%, 30%, and 23%, respectively). Of the 563 patients with NPM1 testing, 58% had an NPM1 mutation. The two treatment groups were generally balanced with respect to the baseline demographics and disease characteristics, except that the placebo arm had a higher percentage of females (59%) than in the midostaurin arm (52%). NPM1 mutations were identified in 55% of patients tested on the midostaurin arm and 60% of patients tested on the placebo arm.

A second course of induction was administered to 25% of the patients, 62% initiated at least one cycle of consolidation, 29% initiated maintenance, and 17% completed all 12 planned cycles of maintenance; 21% of the patients underwent SCT in first CR. The overall rate of SCT (induction failure, first CR or salvage after relapse) was 59% (214/360) of patients in the RYDAPT plus standard chemotherapy arm versus 55% (197/357) in the placebo plus standard chemotherapy arm. All patients were followed for survival.

Efficacy was established on the basis of overall survival (OS), measured from the date of randomization until death by any cause. The primary analysis was conducted after a minimum follow-up of approximately 3.5 years after the randomization of the last patient. RYDAPT plus standard chemotherapy was superior to placebo plus standard chemotherapy in OS [HR 0.77; 95% confidence interval (CI) 0.63, 0.95; 2-sided p = 0.016] (Figure 1). Because survival curves plateaued before reaching the median, median survival could not be reliably estimated.

Figure 1: Kaplan-Meier Curve for Overall Survival in Study 1

The analysis of event-free survival (EFS), defined as a failure to obtain a complete remission (CR) within 60 days of initiation of protocol therapy, or relapse, or death from any cause, showed a statistically significant improvement with a median of 8.2 months for RYDAPT plus standard chemotherapy versus 3.0 months for placebo plus standard chemotherapy with HR 0.78 (95% CI 0.66, 0.93) and 2-sided p = 0.005. In an exploratory analysis of EFS defined as a failure to obtain a CR any time during induction, or relapse, or death from any cause with failures assigned as an event on study Day 1, the median EFS was 10.6 months for RYDAPT plus standard chemotherapy versus 5.6 months for placebo plus standard chemotherapy with HR 0.72 (95% CI 0.61, 0.86).

14.2 Systemic Mastocytosis

Study 2

A single-arm, open-label, multicenter trial evaluated the efficacy of RYDAPT as a single agent in ASM, SM-AHN, and MCL, collectively referred to as advanced SM. The study enrolled 116 adult patients with relapse or progression to 0, 1, or 2 prior regimens for SM. The study excluded patients with serum creatinine > 2.0 mg/dL, hepatic transaminases > 2.5 x ULN or > 5 x ULN if disease-related, total bilirubin > 1.5 x ULN or > 3 x ULN if disease-related, QTc > 450 msec, cardiovascular disease, including left-ventricular ejection fraction < 50%, or any pulmonary infiltrates. In addition, the study excluded patients with acute-stage or life-threatening AHN. Patients received RYDAPT 100 mg orally twice daily in 28-day cycles until disease progression or intolerable toxicity.

Of the 116 patients treated, a study steering committee identified 89 patients who had measurable C-findings and were evaluable for response. The median age in this group was 64 years (range, 25 to 82), 64% of patients were male, and nearly all patients (97%) were Caucasian. Among these patients, 36% had prior therapy for SM, and 82% had the KIT D816V mutation detected at baseline. Their median duration of treatment was 11 months (range, < 1 to 68 months), with treatment ongoing in 17%.

Efficacy was established on the basis of confirmed complete remission (CR) plus incomplete remission (ICR) by 6 cycles of RYDAPT by modified Valent criteria for ASM and SM-AHN (Table 7). Table 7 shows responses to RYDAPT according to modified Valent criteria. Confirmed major or partial responses occurred in 46 of 73 patients with a documented KIT D816V mutation, 7 of 16 with wild-type or unknown status with respect to KIT D816V mutation, and 21 of 32 having prior therapy for SM.

Table 7: Efficacy of RYDAPT in Systemic Mastocytosis per Modified Valent Criteria (Study 2)

Modified Valent Criteria	All Patients Evaluatede (N = 89)	ASM (N = 16)	SM-AHN (N = 57)	MCL (N = 16)
CR + ICR by 6 cycles, n****a,b (95% CI, %)	19 (21%) (13, 31)	6 (38%) (15, 65)	9 (16%) (7, 28)	4 (25%) (7, 52)
**Median duration of CR + ICR (months)**c (95% CI) Ranged	NR (24.1, NE) 6.6+, 65.8+	NR (24.1, NE) 12.1+, 36.8+	NR (7.4, NE) 6.6+, 52.1+	NR (NE, NE) 19.1+, 65.8+
Median time to CR + ICR (months) Range	0.5 0.1, 3.0	0.7 0.3, 1.9	0.5 0.1, 3.0	0.3 0.1, 0.5
Abbreviations: ASM, aggressive systemic mastocytosis; CI, confidence interval; CR, complete remission; ICR, incomplete remission; MCL, mast cell leukemia; NE, not estimated; NR, not reached; SM-AHN, systemic mastocytosis with associated hematological neoplasm. aPer Study Steering Committee. Response confirmation after ≥ 8 weeks was required. No CRs were reported. bPatients who received concomitant high-dose corticosteroids were considered unevaluable and were excluded from response assessment. cAmong patients with a response of CR or ICR. The estimated median follow-up for duration of response (DOR) was 35.4 months overall. dA "+" sign indicates a censored value. e25 patients were not assessable for the presence of MCL on central histopathology review, and 11 patients with unconfirmed presence of AHN were regarded as not having AHN.

As a post-hoc exploratory analysis, efficacy was also assessed using modified 2013 International Working Group-Myeloproliferative Neoplasms Research and Treatment-European Competence Network on Mastocytosis (IWG-MRT-ECNM) consensus criteria. Response after 6 cycles of RYDAPT was determined using a computational algorithm. The efficacy of RYDAPT for MCL was based on the CR results by these criteria. There were 115 patients evaluable for response assessment, of whom 47 (41%) had prior therapy for SM, and 93 (81%) had a documented D816V mutation at baseline. Table 8 provides the results of this analysis. Overall response by modified IWG-MRT-ECNM criteria was reported for 16 (17%) of 93 patients with a documented D816V mutation, and in 8 (17%) of 47 patients having prior therapy for SM.

Table 8: Efficacy of RYDAPT in Systemic Mastocytosis per Modified IWG- MRT-ECNM Consensus Criteria Using an Algorithmic Approach (Study 2)

	All Patients Evaluated (N = 115)b,c	ASM (N = 16)	SM-AHN (N = 72)	MCL (N = 21)	Subtype not Established (N = 6)
Overall response in 6 cycles, n****a (95% CI)	19 (17%) (10, 25)	5 (31%) (11, 59)	8 (11%) (5, 21)	4 (19%) (5, 42)	2 (33%) (4, 78)
Best overall response, n Complete remission Partial remission	2 (2%) 17 (15%)	1 (6%) 4 (25%)	0 (0%) 8 (11%)	1 (5%) 3 (14%)	0 (0%) 2 (33%)
**Duration of response (months)**d Rangee	6.8+, 60.5+	10.2+, 36.4+	6.8+, 51.8+	8.6+, 55.9+	27.3+, 60.5+
Abbreviations: ASM, aggressive systemic mastocytosis; IWG-MRT-ECNM, international working group-myeloproliferative neoplasms research and treatment-european competence network on mastocytosis; MCL, mast cell leukemia; SM-AHN, systemic mastocytosis with associated hematological neoplasm. aDetermined with 12-week confirmation. Patients who received high-dose corticosteroids were considered evaluable for response. bMedian exposure to midostaurin was 11.5 (range, 0.3, 68.3) months. c31 patients were not assessable for MCL on central review, and 15 patients with unconfirmed AHN were classified as not having AHN. dMedian duration of response (DOR) was not reached in any subtype. Median follow up for DOR, among all responders, was 35.0 months. eA “+” sign indicates a censored value.

Study 3

Study 3 was a single-arm, multicenter, open-label trial of 26 patients with advanced SM. RYDAPT was administered orally at 100 mg twice daily with food. The median age in this group was 64 years, 58% of patients were male and most were Caucasian (81%). Eligibility criteria were similar to Study 2. By Valent criteria per investigator assessment, of 17 patients with SM-AHN, 10 achieved a response (1 partial, 9 major) by 2 cycles that was sustained for at least 8 weeks. Patients who received concomitant corticosteroids were included. Of the 6 patients with MCL, 1 achieved partial response and 1 achieved major response. Median duration of response (DOR) for either group had not been reached, with DOR ranging from 3.4+ to 79.2+ months in patients with SM-AHN and 28.6+ to 32.1+ months in patients with MCL. The subtype of SM in the remaining 3 patients was unconfirmed.

11 DESCRIPTION

Midostaurin is a kinase inhibitor for oral use. The molecular formula for midostaurin is C35H30N4O4. The molecular weight is 570.65 g/mol. The chemical name of midostaurin is Benzamide, N-[(9S,10R,11R,13R)-2,3,10,11,12,13-hexahydro-10-methoxy-9-methyl-1-oxo-9,13-epoxy-1H,9H-diindolo[1,2,3-gh:3′,2′,1′-lm]pyrrolo[3,4-j][1,7]benzodiazonin-11-yl]-N-methyl-. The chemical structure of midostaurin is shown below:

RYDAPT is supplied as a soft capsule containing 25 mg of midostaurin. The capsule contains carmine, corn oil mono-di-triglycerides, dehydrated alcohol, ferric oxide red, ferric oxide yellow, gelatin, glycerin 85%, hypromellose 2910, polyethylene glycol 400, polyoxyl 40 hydrogenated castor oil, propylene glycol, purified water, titanium dioxide, and vitamin E.